Intramolecular hydrogen bonding: An opportunity for improved design in medicinal chemistry

Abstract

Recent literature shows that intramolecular hydrogen bond (IMHB) formation can positively impact upon the triad of permeability, solubility, and potency of drugs and candidates. IMHB modulation can be applied to compounds in any chemical space as a means for discovering drug candidates with both acceptable potency and absorption, distribution, metabolism, and excretion‐Tox profiles. Integrating IMHB formation in design of drugs is, therefore, an exciting and timely challenge for modern medicinal chemistry. In this review, we first provide some background about IMHBs from the medicinal chemist's point of view and highlight some IMHB‐associated misconceptions. Second, we propose a classification of IMHBs for drug discovery purposes, review the most common in silico tactics to include IMHBs in lead optimization and list some experimental physicochemical descriptors, which quantify the propensity of compounds to form IMHBs. By focusing on the compounds size and the number of IMHBs that can potentially be formed, we also outline the major difficulties encountered when designing compounds based on the inclusion of IMHBs. Finally, we discuss recent case studies illustrating the application of IMHB to optimize cell permeability and physicochemical properties of small molecules, cyclic peptides and macrocycles.

Can small drugs predict the intrinsic aqueous solubility of ‘beyond Rule of 5’ big drugs?

“…With weakened water binding, the intramolecular H-bond interactions may stabilize the structure in a folded form. In this way, negative enthalpy is consistent with the conformational flexibility of 'molecular chameleons' [26][27][28][29][30][31], and highlights the possible role of sorbed water influences on solubility.…”

“…The observation that the RFR method appears to work encourages us to further search for 3D-based descriptors arising from 'conformational lipophilicity' analysis akin to that developed by Caron and coworkers [27][28][29][30]. The accurate prediction of the solubility of newly approved molecules originating from the bRo5 chemical space would help in selecting/prioritizing candidates in early drug discovery, particularly if the bRo5 molecular basis of solubility were better understood.…”

“…Many of the newly-approved therapeutics are used in immunosuppression, treatment of infectious/viral diseases, and in oncology. Since 2014, an increasing number of 'beyond the Rule of 5' (bRo5) commentaries have stressed that the strict adherence to the Ro5 may result in lost opportunities [21][22][23][24][25][26][27][28][29][30]. Cell-permeable and orally-bioavailable drugs can be discovered far into bRo5 chemical space.…”

“…Nevertheless, concerns have been raised over the expected higher pharmacokinetic risks from bRo5 compounds: low solubility, poor cell permeability, increased cellular efflux, and extensive metabolism. Medicinal chemists have applied tactics to lessen some of the risks: (a) reducing or shielding polarity by N-methylation, or by bulky side chains, (b) selecting compounds with flexible rings structures allowing for conformational lability, and (c) selecting compounds which can reversibly form multiple intramolecular H-bonds (IMHB) to shield polar groups during passage across lipoidal cell barriers, in the manner of 'molecular chameleons' [26][27][28][29][30][31].…”

“…Although most of the bRo5 commentaries have emphasized permeability, absorption, and potency topics, Bergström et al [25] focused on solubility aspects and the promising computational biopharmaceutical modeling strategies to help identify 'formulate-ability' during lead optimization and early development stages of bRo5 compounds. Caron et al [29] considered case studies of kinetic solubility (measured in pH 7.4 phosphate buffer containing 1-5 % DMSO) of bRo5 molecules, in terms of the tendency to form IMHBs and their effect on solubility.…”